The broad objectives of this multifaceted investigation are to achieve greater understanding of the developmentally determined abnormalities in bilirubin metabolism and transport which lead to the regular occurrence of unconjugated hyperbilirubinemia in nearly all human neonates (physiologic jaundice) and the simultaneous dysfunctions which render the newborn susceptible to brain injury from unconjugated bilirubin (kernicterus). The major portion of this study is directed toward developing a thorough understanding of the developmental physiology of intestinal bilirubin absorption and the exogenous and endogenous factors which control the rate of movement of unconjugated bilirubin from the gut lumen into the portal circulation since exaggeration of this pathway has been shown to be a major contributor to physiologic jaundice. The role of human milk from mothers of infants with the breast milk jaundice syndrome will be investigated to determine whether these abnormal milks contribute to exaggeration of intestinal bilirubin absorption and to define the mechanism of this enhancement. Starvation, hypothyroidism and other clinically associated causes of hyperbilirubinemia will also be studied. A rat surgical preparation for quantitative measurement of intestinal bilirubin absorption has been developed and will be used as the central focus of the majority of these studies. The response to pregnancy, hormones and inducing drugs of hepatic glucuronyl transferases and microsomal fluidity in rats and mice will be studied in order to define the mechanism of resistance to induction of the enzyme in pregnant and newborn rat liver. Bilirubin neurotoxicity will be investigated using two methodologic concepts recently developed in experimental animals: classical symptomatology of kernicterus can be produced in newborn rabbits by infusion of bilirubin; and this classical symptomatology is independent of the presence of gross and microscopic evidence of bilirubin deposition in brain. Factors mediating symptomatic bilirubin neurotoxicity and the nature of the morphologic lessions produced by this type of anicteric bilirubin encephalopathy will be studied.